SNAREs in exocytosis and membrane trafficking

Abstract Text: In 1993, Rothman and colleagues sought to explain the specificity of membrane trafficking between cellular compartments by proposing the SNARE hypothesis. Since that time, we have gained significant insights into the conserved mechanisms that control membrane fusion in all eukaryotes. Integral membrane proteins called SNAREs (Soluble NSF Attachment protein Receptors) mediate the membrane fusion that is required to move cargo from one cellular compartment to another. In general, SNAREs on cargo-carrying vesicles are known as v-SNAREs (also called R-SNAREs due to conserved arginines) and those on the destination or target membranes are called t-SNAREs (also called Q-SNAREs due to conserved glutamines). There are large families of both v- and t-SNAREs; all of which contain at least one amphipathic, helical domain that forms a four helical bundle with other SNAREs. This heteromeric complex spans the two membranes to promote lipid mixing for membrane fusion and cargo transfer. Though the significance of their diversity is unclear, certain SNARE combinations (v and t) are optimal for the fusion steps required for specific membrane trafficking steps. For extracellular secretion (exocytosis), t-SNAREs are a heterodimer of syntaxins and SNAP-23/35s. Despite being the minimal components required for fusion, in order for SNAREs to mediate physiologically significant processes, they must be controlled by regulators and post-translational modifications. The regulators affect, where, when, and how fast membrane fusion occurs. Most of the regulators affect the t-SNAREs. Syntaxins are controlled by chaperones of the Sec1/Munc18 (SM) family, which not only stabilize the syntaxins but also guide their binding to other SNAREs. SNARE-23/25s are dynamically anchored in the membranes via thioester-linked acyl groups. SNAP-23 also appears to be acutely controlled by phosphorylation. Regulation of the v-SNAREs appears less wide-spread. Several SNARE accessory proteins have C2 domains that enable calcium-dependent, membrane binding to acidic lipids. Syntaptotagmins are membrane proteins on vesicles thought to be key, calcium sensors that, together with complexins, control the final steps of membrane fusion. Other C2 domain-containing proteins, e.g.,Munc13 family members, are docking factors that bring the two membranes together to engage the SNAREs for subsequent vesicle-target membrane fusion. The Munc13 proteins work with small GTP-binding proteins, called Rabs, to promote docking. Together the SNAREs and SNARE regulators mediate the highly controlled membrane fusion events that underlie many diverse processes such as neurotransmission, hormonal regulation, and hemostasis. 

Keywords: Munc, secretion, SNAREs